Long-term in vitro compatibility of desoximetasone and tacrolimus ointments prompted the current trial in humans. We aimed to evaluate the efficacy of twice-daily simultaneous application of desoximetasone and tacrolimus in the treatment of atopic dermatitis versus tacrolimus monotherapy. Eighty-two subjects were treated in this multicenter, single-group, double-blinded, paired, 3-week follow-up clinical study of desoximetasone 0.25% and tacrolimus 0. 1% ointments versus tacrolimus 0.1% ointment and vehicle. Subjects were treated twice daily for 21 days or until clearing. Safety and efficacy were assessed at days 3, 7, 14, and 21. The combination of desoximetasone and tacrolimus ointment was superior to tacrolimus alone (P=.0002) in treating atopic dermatitis as measured by the summary of the scores for erythema, lichenification, pruritus, scaling/dryness, and oozing/crusting. Of note, pruritus at the application site was diminished in subjects treated with desoximetasone and tacrolimus together compared with tacrolimus alone (P=.04). Combination treatment with desoximetasone and tacrolimus offered increased efficacy and tolerability over tacrolimus alone in patients with atopic dermatitis.